Is MIPEP p.Ser481Phe (c.1442C>T) pathogenic?

MIPEP p.Ser481Phe (c.1442C>T) is classified Uncertain significance in MIPEP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-22). AlphaMissense: likely benign (0.1073); Rare (popmax 0.74%, eas); Associated with lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome.

How common is MIPEP p.Ser481Phe (c.1442C>T) in the general population?

MIPEP p.Ser481Phe (c.1442C>T) is rare (popmax 0.74%, eas) (gnomAD).

What do computational predictors say about MIPEP p.Ser481Phe (c.1442C>T)?

AlphaMissense predicts likely benign (score 0.1073) — an in-silico prediction, not a clinical call.

MIPEP p.Ser481Phe

Q: What condition is associated with MIPEP p.Ser481Phe (c.1442C>T)?

MIPEP p.Ser481Phe (c.1442C>T) is associated with lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome (ClinVar).

Q: How is Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1442C>T · VCV3891666

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1073 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.74%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome

Computational evidence

Protein change
AlphaMissense	0.1073	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -9.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.44	GERP -2.3
Regional constraint	o/e 1.04	unconstrained · MANE · 159 kb · p 0.25 · regional, not allelic
Overall
CADD	15.33	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.74% East Asian · 332/44,880 alleles

Filtering AF 0.674% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.649%

Overall 0.0213% 343/1,613,648 alleles · rare exomes 325/1,461,336 · genomes 18/152,312 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.74%	135
South Asian	0.00659%	15,179
Remaining individualsnot grpmax-eligible	0.0032%	31,241
Admixed American	0.00167%	60,036
European (non-Finnish)	0.00017%	589,776

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MIPEP
Protein: p.Ser481Phe
Coding: c.1442C>T
MANE Select: NM_005932
Type: single nucleotide variant
Location: chr13:23837653 (GRCh38)
Gene constraint: LOEUF 1.181 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.33

Full MIPEP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

MIPEP c.1848+2T>G Likely pathogenic ★★ same condition
MIPEP p.Asp120Asn Likely pathogenic ★★ same condition
MIPEP p.Ala570Thr Uncertain significance ★★ same condition
MIPEP p.Arg202Cys Uncertain significance ★★ same condition
MIPEP p.Arg509His Uncertain significance ★★ ⚠ same condition
MIPEP p.Arg560His Uncertain significance ★★ ⚠ same condition
MIPEP p.Asp168Ala Uncertain significance ★★ ⚠ same condition
MIPEP p.Gln103His Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mipep-p-ser481phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown